The long-term objective of this project is to elucidate the signaling pathways stimulated by osteopontin (OPN) which increase cell survival while also stimulating cancer cell metastasis. Osteopontin interaction with adhesion receptors such as integrins and CD44 mediates many cellular processes, including cell adhesion, migration, proliferation, and survival. The role of OPN in cancer progression is of increasing interest as recent studies have noted that OPN is overexpressed in breast, prostate, and pancreatic cancers;OPN may also be a potential prognostic indicator of metastasis. A key step in elucidating the role of OPN in cancer came when it was shown to increase the activation of PKB/Akt, an important molecule for regulating cell survival and progression. Constitutive activation of Akt is frequently observed in many types of human cancers, the causative role of this kinase as well as the signaling pathway(s) involved in their survival and progression is unknown. This proposal aims to more fully decipher the role of OPN in cancer cell survival and metastasis by first elucidating the roles of the integrin aVp3 and the cell surface receptor CD44 in the regulation of cancer cell survival and progression through Akt. Specific cell receptor inhibitors including SiRNA, and inhibiting antibodies will be used to determine the molecular interactions involved in the initiation of OPN mediated Akt activation. Prostate cancer cells (PCS) have been chosen as a model system due to there ability to express OPN and metastasize to osseous structures, including the mandible. The down stream effects of the engagement of OPN and its cell surface receptors will focus on the cell signaling changes of integrin linked kinase (ILK) and PI3-kinase, two important regulators in the Akt cell survival mechanism. OPN mediated Akt cell survival and metastasis will be further elucidated via using specific molecular inhibitors to ILK and PI3-K while also investigating the role of OPN on their kinase activity. This proposal aims to elucidate metastatic and survival mechanisms by testing the over all hypothesis that the synergistic activity of OPN on its cellular receptors elicits the down stream cell signaling changes via activating the PI3-kinase/Akt and ILK/Akt pathways which play a crucial role in the survival, migration, tumor growth, and metastatic events of cancer cells. Osteopontin is an extracellular matrix protein which has been implicated in the progression of cancer as an important mediator of cell adhesion, migration, proliferation, and survival. Further investigation into the role of osteopontin in cancer may open new doors in clinical medicine by increasing the knowledge of the mechanisms involved in cancer progression and thus providing additional therapeutic targets.